Multiple Sclerosis (MS) is a devastating disease which desperately needs more effective prevention and treatment. MS patients have dysregulated immune responses (GM-CSF, IL-17A and IFNg) as well as alterations in the gut microbiota (increased prevalence of Akkermansia muciniphila) compared to healthy adults. Additionally, findings in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, strongly suggest that the gut microbiota are involved in disease pathogenesis. However, how the gut microbiota including Akkermansia muciniphila (A. muciniphila) influences central nervous system (CNS) autoimmunity remains poorly understood. IL-17A derived from Th17 cells (a,b T cells producing IL-17A and IL-17F) is thought to be a pro- inflammatory cytokine implicated in EAE/MS, but IL-17A also has a beneficial effect in the gut. This differential role of IL-17A in gastrointestinal versus systemic autoimmunity remains unclear. We were first to demonstrate that IL-17A receptor (IL-17RA)-mediated epithelial cell signaling controls microbiota colonization. We found that abrogation of intestinal IL-17RA function contributes to commensal dysbiosis, dysregulated immune cell responses, and predisposition to autoimmunity. However, how intestinal IL-17RA regulation of microbiota modulates systemic autoimmunity remains unclear. The objective of this proposal is to characterize the role of the IL-17A-microbiome including A. muciniphila-CNS axis in regulating autoimmune inflammation, particularly EAE. We have accumulated novel data that lack of intestinal IL-17RA signaling leads to commensal dysbiosis, dysregulated GM-CSF responses as well as an enhanced susceptibility to EAE. Thus, based on our exciting preliminary data, in Aim 1 we propose to investigate how enteric IL-17RA regulation of the microbiome controls EAE. In Aim 2, we will determine whether A. muciniphila dysbiosis regulates fatty acid metabolites, encephalitogenic GM-CSF responses as well as EAE incidence and score in our novel gut epithelial-specific IL- 17RA knockout mice. Upon completion, we will understand the mechanisms for microbiota-Th17 axis in regulating neuroinflammation.